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Literature DB >> 21658961

Discovery of 4-[4-({(3R)-1-butyl-3-[(R)-cyclohexyl(hydroxy)methyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undec-9-yl}methyl)phenoxy]benzoic acid hydrochloride: a highly potent orally available CCR5 selective antagonist.

Rena Nishizawa¹, Toshihiko Nishiyama, Katsuya Hisaichi, Chiaki Minamoto, Masayuki Murota, Yoshikazu Takaoka, Hisao Nakai, Hideaki Tada, Kenji Sagawa, Shiro Shibayama, Daikichi Fukushima, Kenji Maeda, Hiroaki Mitsuya.

Abstract

Based on the original spirodiketopiperazine design framework, further optimization of an orally available CCR5 antagonist was undertaken. Structural hybridization of the hydroxylated analog 4 derived from one of the oxidative metabolites and the new orally available non-hydroxylated benzoic acid analog 5 resulted in another potent orally available CCR5 antagonist 6a as a clinical candidate. Full details of a structure-activity relationship (SAR) study and ADME properties are presented.

Entities: CellLine Chemical Disease Gene Mutation Species

Mesh：

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Year: 2011 PMID： 21658961 PMCID： PMC7604827 DOI： 10.1016/j.bmc.2011.05.022

Source DB: PubMed Journal: Bioorg Med Chem ISSN： 0968-0896 Impact factor: 3.641

25 in total

1. Development of a novel high-throughput surrogate assay to measure HIV envelope/CCR5/CD4-mediated viral/cell fusion using BacMam baculovirus technology.

Authors: Stephen Jenkinson; David C McCoy; Sandy A Kerner; Robert G Ferris; Wendell K Lawrence; William C Clay; J Patrick Condreay; Chari D Smith
Journal: J Biomol Screen Date: 2003-08

Review 2. Small molecule antagonists of the chemokine receptor CCR5.

Authors: Rémy C Lemoine; Jutta Wanner
Journal: Curr Top Med Chem Date: 2010 Impact factor: 3.295

Review 3. Twenty-six years of anti-HIV drug discovery: where do we stand and where do we go?

Authors: Youcef Mehellou; Erik De Clercq
Journal: J Med Chem Date: 2010-01-28 Impact factor: 7.446

4. Identification of a major co-receptor for primary isolates of HIV-1.

Authors: H Deng; R Liu; W Ellmeier; S Choe; D Unutmaz; M Burkhart; P Di Marzio; S Marmon; R E Sutton; C M Hill; C B Davis; S C Peiper; T J Schall; D R Littman; N R Landau
Journal: Nature Date: 1996-06-20 Impact factor: 49.962

5. CC CKR5: a RANTES, MIP-1alpha, MIP-1beta receptor as a fusion cofactor for macrophage-tropic HIV-1.

Authors: G Alkhatib; C Combadiere; C C Broder; Y Feng; P E Kennedy; P M Murphy; E A Berger
Journal: Science Date: 1996-06-28 Impact factor: 47.728

6. The role of a mutant CCR5 allele in HIV-1 transmission and disease progression.

Authors: Y Huang; W A Paxton; S M Wolinsky; A U Neumann; L Zhang; T He; S Kang; D Ceradini; Z Jin; K Yazdanbakhsh; K Kunstman; D Erickson; E Dragon; N R Landau; J Phair; D D Ho; R A Koup
Journal: Nat Med Date: 1996-11 Impact factor: 53.440

7. Spirodiketopiperazine-based CCR5 antagonist: discovery of an antiretroviral drug candidate.

Authors: Rena Nishizawa; Toshihiko Nishiyama; Katsuya Hisaichi; Chiaki Minamoto; Naoki Matsunaga; Yoshikazu Takaoka; Hisao Nakai; Stephen Jenkinson; Wieslaw M Kazmierski; Hideaki Tada; Kenji Sagawa; Shiro Shibayama; Daikichi Fukushima; Kenji Maeda; Hiroaki Mitsuya
Journal: Bioorg Med Chem Lett Date: 2010-12-28 Impact factor: 2.823

8. Spirodiketopiperazine-based CCR5 antagonists: Improvement of their pharmacokinetic profiles.

Authors: Rena Nishizawa; Toshihiko Nishiyama; Katsuya Hisaichi; Keisuke Hirai; Hiromu Habashita; Yoshikazu Takaoka; Hideaki Tada; Kenji Sagawa; Shiro Shibayama; Kenji Maeda; Hiroaki Mitsuya; Hisao Nakai; Daikichi Fukushima; Masaaki Toda
Journal: Bioorg Med Chem Lett Date: 2009-11-12 Impact factor: 2.823

9. Spirodiketopiperazine-based CCR5 inhibitor which preserves CC-chemokine/CCR5 interactions and exerts potent activity against R5 human immunodeficiency virus type 1 in vitro.

Authors: Kenji Maeda; Hirotomo Nakata; Yasuhiro Koh; Toshikazu Miyakawa; Hiromi Ogata; Yoshikazu Takaoka; Shiro Shibayama; Kenji Sagawa; Daikichi Fukushima; Joseph Moravek; Yoshio Koyanagi; Hiroaki Mitsuya
Journal: J Virol Date: 2004-08 Impact factor: 5.103